Obesity and obesity-related diseases are becoming major health problems in many countries. In advanced counties, especially in those in Western Europe, morbidity and mortality due to obesity have been escalating (Non-patent document 1). In recent years, these events have often been discussed in association with the so-called metabolic syndrome, a condition which occurs by accumulation of visceral fat as one of its causal factors.
In such a circumstance, extensive studies are being made on the mechanisms of development of obesity-related diseases, and it is getting clear that incretion compounds which are secreted from adipocytes (adipokines) engage closely in their development. For example, it has been clarified that leptin, adiponectine and resistin, among adipokines, regulate the energy homeostasis of the cells and their sensitivity to insulin (Non-patent documents 2 and 3). Further, adipocytes secrete inflammatory cytokines, which have long been known to be secreted from macrophages, such as TNF-α, and proteins like MCP-1, which plays a role in obtaining resistance to insulin (lowering sensitivity of the cells to insulin) (Non-patent documents 4 and 5). These compounds also may be regarded as a kind of adipokines. In addition to these, many other adipokines have been observed to be expressed in the course of differentiation of preadipocytes into adipocytes.
As mentioned above, clarifying the functions of adipokines secreted from adipocytes is very important for elucidation of the etiology of obesity-related diseases including diabetes and the so-called metabolic syndrome, and further for the development of effective, new ways of treating them.
Among obesity-related diseases, the number of patients with diabetes exceeds 7 million in Japan alone, and the number is increasing rapidly. In other developed countries also, the situation is largely the same as that in Japan. Diabetes is a systemic disorder of metabolism caused by abnormal increase in blood sugar levels due to a lowered ability of regulating blood sugar levels (glucose tolerance), and is characterized in that it extremely deteriorates the quality of life (QOL) not only by causing severe metabolic disorders like hyperosmolar coma and ketoacidosis, but also by leading to bad prognosis due to microangiopathic complications. Diabetes is generally classified into type 1 diabetes, which is caused by destruction of pancreatic β-cells (autoimmune disorders are considered to be the primary cause), and type 2 diabetes, which is a combination of insulin resistance and reduction in insulin secretion.
In type 2 diabetes, which accounts for about 90% of diabetic patients, the insulin action is weakened through a combination at varying proportions of lowered insulin secretion from pancreatic β-cells and insulin resistance in those cells which insulin targets, such as those in skeletal muscles, resulting in hyperglycemia. Besides, persistent insulin resistance leads to a vicious circle of β-cells being exhausted to further weaken in its ability of secreting insulin, thus the symptoms exacerbate. For type 2 diabetes, it is expected that such agents that can reduce insulin resistance would work very effectively, for they could terminate the vicious cycle.
As therapeutics for type 2 diabetes, mitiglinide calcium hydrate tablets (trade name: Glufast tablets), and pioglitazone hydrochloride tablets (trade name: Actos tablets) are already on the market. However, it is not yet possible to address all the patient with type 2 diabetes whose etiology is not fully understood and which has a variety of backgrounds. Thus, development of novel agents have been hoped for which have a different mechanism of action from those of conventional ones.
Chemerin (also called TIG2 or metabokine) is a chemotactic factor for macrophages and non-differentiated dendritic cells, and is a ligand for the G protein-coupled receptor (ChemR23) (Non-patent documents 6 and 7). It is reported that chemerin, as a chemotactic factor for a specific population of immunomodulatory antigen presenting cells, has a function to regulate immune responses at sites of inflammation and injury (Non-patent documents 8 and 9).
Human chemerin is translated as a protein consisting of 163 amino acids, and after secreted as a precursor produced by processing at its signal peptide consisting of 20 amino acid at its N-terminus (human prochemerin) (its nucleotide sequence shown as SEQ ID NO:1 and amino acid sequence as SEQ ID NO:2, respectively), 6 amino acids at its C-terminus (amino acid sequence: Lys-Ala-Leu-Pro-Arg-Ser: SEQ ID NO:3) is removed to form human mature chemerin (its nucleotide sequence shown in SEQ ID NO:4 and amino acid sequence in SEQ ID NO:5) consisting of 137 amino acids and having high affinity for ChemR23 (Non-patent documents 7 and 10).
Recently, it has been reported that chemerin is a member of adipokines, which take part in differentiation of adipocytes (Non-patent document 11), and that the blood concentration of chemerin corresponds with body mass index (BMI), triglycerides concentration in blood, and blood pressure (Non-patent document 12). However, the role of chemerin in regulation of metabolism has not been elucidated.    [Non-patent document 1] Nature, 414:782-7 (2001)    [Non-patent document 2] J Allergy Clin Immunol, 115: 911-9 (2005); quiz 920    [Non-patent document 3] Endocrinol Metab, 89: 2548-56 (2004)    [Non-patent document 4] Circ Res, 95: 858-66 (2004)    [Non-patent document 5] Annu Rev Immunol, 18: 217-42 (2000)    [Non-patent document 6] J Invest Dermatol, 109: 91-5 (1997)    [Non-patent document 7] J Exp Med, 198: 977-85 (2003)    [Non-patent document 8] J Biol Chem, 280: 34661-6 (2005)    [Non-patent document 9] J Immunol, 174: 244-51 (2005)    [Non-patent document 10] J Biol Chem, 279: 9956-62 (2004)    [Non-patent document 11] J Biol Chem, 282: 28175-88 (2007)    [Non-patent document 12] Endocrinology, 148: 4687-94 (2007)